Insight of endophytic fungi promoting the growth and development of woody plants.

Microorganisms play an important role in plant growth and development. In particular, endophytic fungi is one of the important kinds of microorganisms and has a mutually beneficial symbiotic relationship with host plants. Endophytic fungi have many substantial benefits to host plants, especially for woody plants, such as accelerating plant growth, enhancing stress resistance, promoting nutrient absorption, resisting pathogens and etc. However, the effects of endophytic fungi on the growth and development of woody plants have not been systematically summarized. In this review, the functions of endophytic fungi for the growth and development of woody plants have been mainly reviewed, including regulating plant growth (e.g., flowering, root elongation, etc.) by producing nutrients and plant hormones, and improving plant disease, insect resistance and heavy metal resistance by producing secondary metabolites. In addition, the diversity of endophytic fungi could improve the ability of woody plants to adapt to adverse environment. The components produced by endophytic fungi have excellent potential for the growth and development of woody plants. This review has systematically discussed the potential regulation mechanism of endophytic fungi regulating the growth and development of woody plants, it would be of great significance for the development and utilization of endophytic fungi resource from woody plants for the protection of forest resources.

CircularRNA Hsa_circ_0093335 promotes hepatocellular carcinoma progression via sponging miR-338-5p.

Circular RNAs play an important role in the development of various malignancies, including hepatocellular carcinoma (HCC). Nevertheless, the role of Hsa_circ_0093335 (circ0093335) in HCC has not yet been explored. To investigate the biological effects and molecular mechanisms of circ0093335 on HCC. Circ0093335 expression was detected in HCC cells and clinical specimens using qRT-PCR. The association between circ0093335 expression and HCC patients' clinical characteristics was determined using SPSS. The role of circ0093335 in HCC was estimated by overexpression and knockdown experiments in vitro and in vivo. qRT-PCR, nucleoplasma separation assay, FISH assay, RIP, dual luciferase reporter assay and rescue assay were used to validate the regulatory effect of circ0093335 on miR-338-5p. The study findings showed that circ0093335 was upregulated in HCC. High circ0093335 expression was linked with the tumour-node-metastasis stage and microvascular tumour invasion. circ0093335 is greatly involved in HCC cell proliferation, aggressive ability and mouse tumour growth, according to many in vitro and in vivo tests. Mechanistically, circ0093335 downregulated miR-338-5p expression by sponging, consequently promoting HCC progression. Our research indicated that circ0093335 might be a target for HCC therapy since it promotes tumour progression by acting as a miR-338-5p 'sponge'.

Comprehensive phytochemical analysis of lingonberry (Vaccinium vitis-idaea L.) from different regions of China and their potential antioxidant and antiproliferative activities.

Lingonberry are underutilised due to the lack of evaluating active compounds in different parts. In this study, the phytochemical profiles, antioxidant and antiproliferative activities of lingonberry's fruits, leaves and stems from different regions of China were compared. Ninety-five bioactive compounds were rapidly identified using a molecular network based on UPLC-Q-Exactive Orbitrap mass spectrometry. The UPLC-QqQ-MS/MS method combined with principal component analysis (PCA) quantified 18 bioactive components in 6 classes. The highest content of arbutin (15 mg/100 g DW) was found in leaves of Huzhong (P6). Ursolic acid and cyanidin-3-O-galactoside were highest in fruits of Tahe (P4) (4.5 mg/100 g DW and 3.2 mg/100 g DW, respectively). Antioxidant activities determined by DPPH, ABTS+ and FRAP methods were significantly correlated with total phenolic content (TPC), total flavonoid content (TFC) and total anthocyanin content (TAC). The results indicate that the strongest antioxidant activity and antiproliferative efficacy are observed in the fruits of Tahe (P4) and leaves of Huzhong (P6), respectively. Our results provide valuable insights into lingonberry's comprehensive development and utilization.

Upgrading the accumulation of ginsenoside Rd in Panax notoginseng by a novel glycosidase-producing endophytic fungus G11-7.

A novel endophytic fungus producing beta-glucosidase was isolated and characterized from pigeon pea (Cajanus cajan [L.] Millsp.), which has excellent properties in converting ginsenoside Rb1 to ginsenoside Rd in Panax notoginseng. According to the 16S rDNA gene sequence, the G11-7 strain was identified as Fusarium proliferatum, and the accession number KY303906 was confirmed in GenBank. The G11-7 immobilized spores, in which the activity of beta-glucosidase could reach 0.95 U/mL, were co-cultured with P. notoginseng plant material to obtain a continuous beta-glucosidase supply for the biotransformation of ginsenoside Rb1 to Rd. Under the liquid-solid ratio (20:1), initial pH (6.0), and temperature (30 °C) constituents, the maximum ginsenoside Rd yield was obtained as 9.15 ± 0.65 mg/g, which was 3.67-fold higher than that without fungal spore co-culture (2.49 ± 0.98 mg/g). Furthermore, immobilized G11-7 spores showed significant beta-glucosidase producing ability which could be recovered and reused for 6 cycles. Overall, these results suggested that immobilized G11-7 offered a promising and effective approach to enhance the production of ginsenoside Rd for possible nutraceutical and pharmaceutical uses.

Genome-wide transcriptome analysis and characterization of the cytochrome P450 flavonoid biosynthesis genes in pigeon pea (Cajanus cajan).

MAIN CONCLUSION: 226 CcCYP450 genes were identified at the genomic level and were classified into 45 clades based on phylogenetic analysis. CcCYP75B165 gene was found that might play important roles in the biosynthesis of flavonoids in pigeon pea, and was significantly induced by methyl jasmonate (MeJA). The cytochrome P450 mono-oxygenase (CYP450) superfamily plays a key role in the flavonoid biosynthesis pathway and resists different kinds of stresses. Several CYP450 genes have been identified to be involved in the biosynthesis of crop protection agents. However, the CcCYP450 genes from pigeon pea have not been identified. Here, 226 CcCYP450 genes were identified at the genomic level by analysing the gene structure, distribution on chromosomes, gene duplication, and conserved motifs and were classified into 45 clades based on phylogenetic analysis. RNA-seq analysis revealed clear details of CcCYP450 genes that varied with time of MeJA (methyl jasmonate) induction. Among them, six CcCYP450 subfamily genes were found that might play important roles in the biosynthesis of flavonoids in pigeon pea. The overexpression of CcCYP75B165 in pigeon pea significantly induced the accumulation of genistin and downregulated the contents of cajaninstilbene acid, apigenin, isovitexin, and genistein and the expression of flavonoid synthase genes. This study provides theoretical guidance and plant genetic resources for cultivating new pigeon pea varieties with high flavonoid contents and exploring the molecular mechanisms of the biosynthesis of flavonoids under MeJA treatment.

Cryptochlorogenic acid attenuates LPS-induced inflammatory response and oxidative stress via upregulation of the Nrf2/HO-1 signaling pathway in RAW 264.7 macrophages.

Phenolic acids are found in natural plants, such as caffeic acid, rosmarinic acid, and chlorogenic acid. They have long been used as pharmacological actives, owing to their anti-inflammatory and antioxidant activities. Cryptochlorogenic acid (CCGA) is a special isomer of chlorogenic acid; the pharmacological effects and related molecular mechanisms of CCGA have been poorly reported. In the present study, the antioxidant and anti-inflammatory effects of CCGA in RAW 264.7 macrophages and the underlying mechanisms were investigated. The results revealed that CCGA dose-dependently inhibited LPS-induced production of NO, TNF-α, and IL-6 and blocked iNOS, COX-2, TNF-α, and IL-6 expressions. CCGA also significantly increased the GSH/GSSG ratio and SOD activity and reduced the MDA level. Moreover, CCGA suppressed the nuclear translocation of NF-κB by hindering the phosphorylation of IκB kinase (IKK) and degrading IκB. It also downregulated the phosphorylation of MAPKs. Our results indicated that CCGA significantly inhibited NF-κB activation by controlling the expression of pro-inflammatory factors and promoting the nuclear transfer of Nrf2. In conclusion, CCGA could attenuate LPS-induced inflammatory symptoms by modulating NF-κB/MAPK signaling cascades and inhibit LPS-induced oxidative stress via Nrf2 nuclear translocation.

Identification of quinoxalin-2(1H)-one derivatives as a novel class of multifunctional aldose reductase inhibitors.

Aim: Targeting aldose reductase and oxidative stress with quinoxalin-2(1H)-one derivatives having a 1-hydroxypyrazole head as the bioisosteric replacement of carboxylic acid. Methodology & results: Aldose reductase inhibition, selectivity and antioxidant potency of all the synthesized compounds were evaluated, and binding modes were studied by molecular docking. Most of the derivatives showed potent and selective aldose reductase inhibition, and among them 13d was the most active (IC50 = 0.107 µM), suggesting success of the bioisosteric strategy. Phenolic 3,4-dihydroxyl compound 13f showed strong antioxidant ability even comparable to that of the well-known antioxidant Trolox. Conclusion: The present study identified the excellent bioisostere of the 1-hydroxypyrazole head group along with phenolic hydroxyl and vinyl spacer in C3 side chain on constructing quinoxalinone-based multifunctional aldose reductase inhibitors.

Pre-feasibility Study for Establishing Radioisotope and Radiopharmaceutical Production Facilities in Developing Countries.

BACKGROUND: A significant number of developing countries have no facilities to produce medical radioisotopes and radiopharmaceuticals. OBJECTIVE: In this paper we show that access to life-saving radioisotopes and radiopharmaceuticals and the geographical distribution of corresponding infrastructure is highly unbalanced worldwide. METHODS: We discuss the main issues which need to be addressed in order to establish the production of radioisotopes and radiopharmaceuticals, which are especially important for developing countries as newcomers in the field. The data was gathered from several sources, including databases maintained by the International Atomic Energy Agency (IAEA), World Health Organization (WHO), and other international organizations; personal interactions with representatives in the nuclear medicine field from different regions of the world; and relevant literature. RESULTS: Developing radioisotope and radiopharmaceutical production program and installing corresponding infrastructure requires significant investments, both man-power and financial. Support already exists to help developing countries establish their medical radioisotope production installations from several organizations, such as IAEA. CONCLUSION: This work clearly shows that access to life-saving radioisotopes and the geographical distribution of corresponding infrastructure is highly unbalanced. Technology transfer is important as it not only immediately benefits patients, but also provides employment, economic activity and general prosperity in the region to where the technology transfer is implemented.

Synthesis of benzothiadiazine derivatives exhibiting dual activity as aldose reductase inhibitors and antioxidant agents.

Several multifunctional benzothiadiazine derivatives were synthesized and examined for their inhibition to the enzyme aldose reductase and in vitro antioxidant activity to identify novel drugs for diabetes and its complications. Most of them exhibited good inhibitory activity. Importantly, a number of compounds demonstrated strong antioxidant activity and one compound in particular was extremely active in the DPPH radical scavenging and MDA inhibition analysis. The DPPH radical scavenging rate with this compound was 98.0%, 92.3% and 42.1% at concentrations of 100µM, 10µM, and 1µM, respectively, and the initial reaction rate was faster than Trolox at a concentration of 10µM.

Pyridothiadiazine derivatives as aldose reductase inhibitors having antioxidant activity.

A series of aldose reductase (ALR2) inhibitors based on pyridothiadiazine were prepared and evaluated for their activities in ALR2 inhibition, DPPH scavenging, and MDA inhibition. Comparison studies were carried out between analogs having either hydroxyl or methoxy groups substituted on the N2-benzyl side chains of the compounds. Most of the hydroxy-substituted compounds were found to be more potent compared to their methoxy-substituted analogs with respect to DPPH inhibition (>93%) and MDA inhibition (>73%). However, ALR2 inhibitory activity was found to be affected by the electron-withdrawing substituent at the C7 position in addition to the effect of the N2-substituted benzyl group. These results provide an array of multifunctional ALR2 inhibitors possessing capacities both for ALR2 inhibition and as antioxidants.

Phenolic 4-hydroxy and 3,5-dihydroxy derivatives of 3-phenoxyquinoxalin-2(1H)-one as potent aldose reductase inhibitors with antioxidant activity.

A group of novel quinoxalinone derivatives (4a-h) were prepared and investigated for their inhibitory activity against ALR2 and antioxidant activity. Most of them were found to be potent aldose reductase inhibitors with IC50 values ranging from 0.019 to 0.982 µM. The most active compound 2-(3-(4-hydroxyphenoxy)-6-fluoro-2-oxoquinoxalin-1(2H)-yl)acetic acid (4c) also had an excellent selectivity. In addition, a number of compounds showed strong antioxidant activity and the phenolic 3,5-dihydroxyl compound 4f with 7-chloro in the quinoxalinone core was most active in scavenging the DPPH radical and suppressing lipid peroxidation.

Design and synthesis of potent and multifunctional aldose reductase inhibitors based on quinoxalinones.

Quinoxalin-2(1H)-one based design and synthesis produced several series of aldose reductase (ALR2) inhibitor candidates. In particular, phenolic structure was installed in the compounds for the combination of antioxidant activity and strengthening the ability to fight against diabetic complications. Most of the series 6 showed potent and selective effects on ALR2 inhibition with IC50 values in the range of 0.032-0.468 µM, and 2-(3-(2,4-dihydroxyphenyl)-7-fluoro-2-oxoquinoxalin-1(2H)-yl)acetic acid (6e) was the most active. More significantly, most of the series 8 revealed not only good activity in the ALR2 inhibition but also potent antioxidant activity, and 2-(3-(3-methoxy-4-hydroxystyryl)-2-oxoquinoxalin-1(2H)-yl)acetic acid (8d) was even as strong as the well-known antioxidant Trolox at a concentration of 100 µM, verifying the C3 p-hydroxystyryl side chain as the key structure for alleviating oxidative stress. These results therefore suggest an achievement of multifunctional ALR2 inhibitors having both potency for ALR2 inhibition and as antioxidants.

Chiral resolution, determination of absolute configuration, and biological evaluation of (1,2-benzothiazin-4-yl)acetic acid enantiomers as aldose reductase inhibitors.

A novel series of (1,2-benzothiazin-4-yl)acetic acid enantiomers was prepared by chiral resolution, and their absolute configurations were determined using the PGME method. The biological evaluation of the racemate and single enantiomers has shown a remarkable difference for the aldose reductase inhibitory activity and selectivity. The (R)-(-)-enantiomer exhibited the strongest aldose reductase activity with an IC(50) value of 0.120 µM, which was 35 times more active than the S-(+)-enantiomer. Thus, the stereocenter at the C4 position of this scaffold was shown to have a major impact on the activity and selectivity.

Copper-catalyzed asymmetric synthesis and comparative aldose reductase inhibition activity of (+)/(-)-1,2-benzothiazine-1,1-dioxide acetic acid derivatives.

A copper catalyst system for the asymmetric 1,4-hydrosilylation of the α,ß-unsaturated carboxylate class was developed by which synthesis of (+)- and (-)-enantiomers of 1,2-benzothiazine-1,1-dioxide acetates has been achieved with a good yield and an excellent level of enantioselectivity. A comparative structure-activity relationship study yielded the following order of aldose reductase inhibition activity: (-)-enantiomers > racemic > (+)-enantiomers. Further, a molecular docking study suggested that the (-)-enantiomer had significant binding affinity and thus increased inhibition activity.

Structure-activity relationships studies of quinoxalinone derivatives as aldose reductase inhibitors.

Novel quinoxalinone derivatives were synthesized and tested for their inhibitory activity against aldose reductase. Among them, N1-acetate derivatives had significant activity in a range of IC50 values from low micromolar to submicromolar, and compound 15a bearing a C3-phenethyl side chain was identified as the most potent inhibitor with an IC50 value of 0.143 µM. The structure-activity studies suggested that both C3-phenethyl and C6-NO2 groups play an important role in enhancing the activity and selectivity of the quinoxalinone based inhibitors.

Novel synthesis of nitro-quinoxalinone derivatives as aldose reductase inhibitors.

A novel, non-acid series of nitroquinoxalinone derivatives was synthesized and tested for their inhibitory activity against aldose reductase as targeting enzyme. All active compounds displayed an 8-nitro group, and showed significant activity in IC50 values ranging from 1.54 to 18.17 µM. Among them 6,7-dichloro-5,8-dinitro-3-phenoxyquinoxalin-2(1H)-one (7e), exhibited the strongest aldose reductase activity with an IC50 value of 1.54 µM and a good SAR (structure-activity relationship) profile.

Synthesis and structure-activity relationship studies of quinoxaline derivatives as aldose reductase inhibitors.

ARIs for diabetes: A series of 2-(3-benzyl-2-oxoquinoxalin-1(2H)-yl)acetic acid derivatives were designed and synthesized as inhibitors of aldose reductase (AR), a novel target for the treatment of diabetes complications. Most of the derivatives proved to be potent and selective, with IC50 values in the low nanomolar to micromolar range.

An efficient synthesis of quinoxalinone derivatives as potent inhibitors of aldose reductase.

A novel and facile synthesis of quinoxalinone derivatives was developed in which a wide range of 3-chloroquinoxalin-2(1H)-ones as key intermediates can be generated chemo- and regioselectively in good yields from corresponding quinoxaline-2,3(1H,4H)-diones. This new protocol is arguably superior, as it allows the design and preparation of a variety of bioactive quinoxaline-based compounds, which are particularly effective in the treatment of diabetes and its complications. Through this procedure, a new class of quinoxalinone-based aldose reductase inhibitors were synthesized successfully. Most of the inhibitors, with an N1-acetic acid head group and a substituted C3-phenoxy side chain, proved to be potent and selective. Their IC(50) values ranged from 11.4 to 74.8 nM. Among them, 2-(3-(4-bromophenoxy)-7-fluoro-2-oxoquinoxalin-1(2H)-yl)acetic acid and 2-(6-bromo-3-(4-bromophenoxy)-2-oxoquinoxalin-1(2H)-yl)acetic acid were the most active. Structure-activity relationship and molecular docking studies highlighted the importance of the ether spacer in the C3-phenoxy side chains, and provided clear guidance on the contribution of substitutions both at the core structure and the side chain to activity.